N-oxides of phenothiazine compounds



United States Patent Ofitice 3,341,533 Patented Sept. 12, 1967 Thisinvention relates to new chemical compounds and more particularly to newN-oxides of certain phenothiazine compounds.

The new compounds of this invention include bases of the Formula 1:

and acid-addition salts thereof, wherein X is hydrogen, halogen(preferably chloro), lower alkyl, lower cycloalkyl (e.g., cyclopropyland cyclobutyl), lower alkoxy, lower cycloalkoxy (e.g., cyclopropyl andcyclobutoxy), lower alkanoyl, lower alkyl mercapto,trifiuorornethylmercapto, lower alkylsulfonyl ,N,N-di-loweralkylsulfonamido, cyano and optimally trifiuoromethyl; A and A are eachlower alkylene, preferably of two to three carbon toms; n and Ir is oneor two; and R is hydrogen or an acyl radical of a hydrocarbon carboxylicacid or dicarboxylic acid. The preferred hydrocarbon carboxylic acidsinclude the alkanoic acids (e.g., acetic, propionic, enanthic, decanoicand lauric acid), the alkenoic acids (e.g., undecyclenic, oleic andZ-heptenoic acid), the alkynoic acids, the alkanedienoic acids (e.g.,heptadienoic acid), aryl carboxylic acids (e.g., benzoic acid),cycloalkane carboxylic acids, aryl alkanoic acids (e.g., phenacetic andfi-phenyl propionic acid), cycloalkene carboxylic acids and thealkanedioic acids (e.g., succinic, glutaric, adipic and azelaic acid).

Among the acids useful in preparing the acid-addition salts may bementioned the non-toxic pharmaceuticallyacceptable inorganic and organicacids, such as the hydrohalic acids (e.g., ydrochloric and hydrobromicacid), sulfuric acid, nitric acid, phosphoric acid, oxalic acid,tartaric acid, citric acid, pamoic acid, furnaric acid, acetic acid,rnaleic acid and succinic acid.

The new compounds of this invention are physiologically activesubstances that possess tranquilizing activity and hence may beadministered perorally or parenterally in the same manner as and in lieuof known tranquilizing agents. Unlike the N-oxides of othertranquilizing agents, such as the N-oxide of-(3dirnethylaminopropyl)-2-trifluoromethylphenothiazine, which has onlyabout onefourth the tranquilizing activity of 10-(3-dimethylaminopropyl) 2 trifluoromethylphenothiazine, it has beensurprisingly found that the N-oxides of this invention retain the fullpotency of the parent compounds from which they are formed.

To prepare the compounds of this invention, compounds of the Formula II:

n and R are as hereinbefore defined, in the form of its free base, areinteracted with hydrogen peroxide to yield the final products of thisinvention in the form of their free bases. If an acid-addition salt isdesired, the free bases are then reacted with the desired acid in theusual manner.

Among the suitable starting compound of Formula II may be mentioned:

wherein X, A, A, n,

10- N Z-hydroxyethyl) piperazinoethyl] -phenothiazine,

1'0- [3 N (Z-hydroxyethyl) piperazino1propyl] phenothiazine,

1 0-[N [3- (3 -hydroxypropyl) piperazino] propyl] phenothiazine,

10- 3- [N Z-hydroxyethyl) piperazino] propyl] -2- chlorophenothiazine,

10- 3- [N Z-hydroxyethyl piperazino] propyl] -2- methyl phenothiazine,

10- [3 [N Z-hydroxyethyl piperazino propyl] -2-cyclopropylphenothiazine,

l 0- [3- [N (Z-hydroxyethyl)piperazino1propyl] -2- methoxyphenothiazine,

10- [3-[N (Z-hydroxyethyl)piperazino1propyl] -2- acetylphenothiazine,

10- [3-[N (Z-hydroxyethyl)piperazino1propyl] -2- cyanophenothiazine,

l0-[3-[N -(2-hydroxyethy])piperazino1propyl1-2-methylmercaptophenothiazine,

10- [3- N Z-hydroxyethyl piperazino] propyl] -2- N,N'-dimethylarninosulfonyl) phenothiazine,

10' [3 N 2-hydroxyethyl piperazino] propyl-2-trifluoromethylmercaptophenothiazine,

10- [3 N Z-hydroxyethyl piperazino] propyl-Z-methylsulfonylphenothiazine,

10- 3 N (Z-hydroxyethyl piperazino] propyl-Z-trifluorornethylphenothiazine,

10- [3 [N Z-acetoxyethyl piperazino] pro pyl] -2-trifluoromethylphenothiazine,

l 0- [3 N 2- Z-hydroxyethoxy) ethyl] piperazino] propyl]-2-trifiuoromethylphenothiazine,

10- 3 [N [2- (2acet0xyethoxy) ethyl] piperazino] propyl]-2-trifiuoromethylphenothiazine.

10- 3- N Z-heptanoyloxyethyl piperazino] propyl]2-trifluoromethylphenothiazine,

10-[3 [N (Z-decanoyloxyethyl piperazino] propyl]2trifluoromethylphenothiazine,

l0- [3 [N 2-undecenoyloxyethyl piperazino] propyl]2-trifluoromethylphenothiazine,

azelaoylbis 10-[3 [4- (Z-hydroxyethyl piperazino] propyl]-2-thriiluoromethylphenothiazine] 10- [2- [N (3 -hydroxypropyl)piperazino] ethyl] -2- trifiuoromethylphenothiazine, and

10- 3 [N Z-bcnzoyloxyethy-l piperazino] propyl] -2-trifluoromethylphenothiazine.

The following examples illustrate the invention (all temperatures beingin centigrade):

' EXAMPLE l ]0 [3- [N (Z-hydroxyethyl) piperazino] propyl]-2-triflzzoromethylphenothiazine N -oxide hydrochloride EXAMPLE 210-[3-[N -(Z-hydroxyethyl)piperazino]prpyl1-2- chloro-phenothiazine N-0xide hydrochloride By substituting 18.5 g. of 10-[3-[N-(2-hydroxyethyl) piperazinoJpropyl]-2-chlorophenothiazine for the 20.2g. of 10 [3 [N -(2-hydroxyethyl)piperazino]propyl]-2-trifiuoromethylphenothiazine in Example 1 and carrying out the proceduretherein described, there is obtained the above named product.

EXAMPLE 3 10-[3- [N -(2-hydr0xyethyl)piperazin01propyl] -2-methoxyphenothiazine N -oxide hydrochloride By substituting 18.3 g. of10-[3-[N -(2-hydroxyethyl) piperazinoJpropyl]-2-meth0xyphenothiazine forthe 20.2 g. of 10 [3-[N -(2hydroxyethyl)piperazino]propyl]-2-trifiuoromethylphenothiazine in Example 1 and performing the proceduretherein described, there is obtained the above named product.

EXAMPLE 4 10-[3- [N (Z-heptanoyloxyethyl)piperazino] propyl] -2-trifluoromethylphenothiazine N -0xide hydrochloride By substituting 25.8g. of 10-[3-[N -(2-heptanoyloxyethyl)piperazino]propyl] 2trifiuoromethylphenothiazine for the 20.2 g. of 10-[3-[N-(2-hydroxyethyl) piperazino] propyl]-2-trifluoromethylphenothiazine inExample 1, and proceeding as described therein, there is obtained theabove named product.

EXAMPLE 5 [3- [N (Z-decanoyloxyethyl) piperazino] propyl] -2- trifluoromethylphenothiazine N -0xide hydrochloride By substituting 27.9 g. of10-[3-[N -(2-decanoy1oxyethyl)piperazino]propyl] 2trifiuoromethylphenothiazine for the 20.2 g. of 10-[3-[N-(2-hydroxyethyl)piperazino]propyl] 2 trifluorornethylphenothiazine inExample l and proceding as described therein, there is obtained theabove named product.

The invention may be variously otherwise embodied within the scope ofthe appended claims.

What is claimed is: 1. A compound selected from the group consisting ofa base of the formula and a non-toxic pharmaceutically acceptableacid-addition salt thereof, wherein X is selected from the groupconsisting of hydrogen, halogen, lower alkyl, lower cycloalkyl, loweralkoxy, lower cycloalkoxy, lower alkanoyl, lower alkylmercapto,trifluoromethylmercapto, lower alkylsulfonyl, di-lower alkylsulfonamido,cyano and trifluoromethyl; A and A are each lower alkylene; n and n areintegers selected from the group consisting of one and two; and R isselected from the group consisting of hydrogen, and, when n is 1, theacyl radical of an acid selected from the group consisting of al'kanoicacid having two to twelve carbon atoms, alkenoic acid having three toeighteen carbon atoms, alkanedienoic acid having seven carbon atoms,benzoic acid, and phenyl (lower alkanoic) acid, and when n is 2, theacyl radical of an alkanedioic acid having four to nine carbon atoms.

2. 10 [3-[N -(2-hydroxyethyl)piperazino]propyl]-2-trifluoromethylphenothiazine N -oxide.

3. A non-toxic pharmaceutically acceptable acid addition salt of thecompound of claim 2.

4-. The hydrochloride salt of the compound of claim 2.

5. 10 [3 [N (2 heptanoyloxyethyl)piperazino] propyl]-2-trifluoromethylphenothiazine N -oxide.

6. 10 [3 [N (2 clecanoyloxyethyl]piperazino]propyl]-2-trifluoromethylphenothiazine N -oxide.

References Cited UNITED STATES PATENTS 1/1960 Ullyot 260-243 OTHERREFERENCES WALTER A. MODANCE, Primary Examiner. HARRY I. MOATZ,Assistant Examiner.

